Broad neutralization capability of potent nanobody against SARS-CoV-2 variants

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Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, millions of individuals worldwide have been infected by the virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This is a highly infectious RNA virus belonging to the family Coronaviridae, and, to date, it has claimed more than 5 million lives globally. This pandemic has drastically affected the world’s healthcare system and economy.

Study: Nebulized delivery of a broadly neutralizing SARS-CoV-2 RBD-specific nanobody prevents clinical, virological and pathological disease in a Syrian hamster model of COVID-19. Image Credit: Juan Gaertner/ Shutterstock

Scientists and healthcare policymakers are working at a record speed to develop various pharmaceutical and non-pharmaceutical measures to contain the COVID-19 pandemic. Owing to the rapid evolution of the virus, the efficacy of the available COVID-19 vaccines has been threatened; this has further created the need for the development of effective therapeutics that could be effective against SARS-CoV-2 variants. Scientists have highlighted the effectiveness of treatments using antibody treatment from convalescent patient-derived plasma or with recombinant monoclonal antibodies delivered intravenously against acute SARS-CoV-2 infection.

Although these treatments have the potential for nebulized delivery, they are relatively expensive treatments that limit their global use. Scientists believe that utilizing low-cost adjunct therapeutics could mitigate the problem. SARS-CoV-2 is a respiratory disease, and, therefore, the development of inhaled treatments may result in lower dose requirements as the virus could be inhibited at the site of early infection.

Background

Members of the Camelidae family, such as IIamas, camels, and alpacas, consist of a type of immunoglobulin that has paired heavy chains with antigen-binding variable domains. These single-domain monovalent antigen-binding domains are small in size (12-15 kDa) and reveal a high affinity towards the target antigen. These are known as nanobodies, which can be easily expressed in different expression systems, for example, bacteria, yeast, and mammalian cell lines. One of the extraordinary features of nanobodies is their stability in a wide-ranging pH and temperature. Additionally, these can easily be lyophilized and aerosolized. Therefore, scientists have developed nanobody therapies that involve nebulization delivery in treating respiratory diseases.

Previous studies have shown that nanobodies can actively neutralize SARS-CoV-2. Previous research associated with the isolation and characterization of a SARS-CoV-2 RBD binding nanobody (NIH-CoVnb-112) revealed that it possesses strong biophysical properties and binds to RBD with a low nanomolar affinity. This showed that nanobodies could be effectively used in the future to develop novel COVID-19 therapeutics and diagnostics.

A new study published on bioRxiv* has described the molecular basis of the neutralization potency and breadth of nanobodies (CoVnb-112). It has also determined the crystalline structure of the NIH-CoVnb-112 complex with the SARS-CoV-2 RBD under 2.8 Å resolution.

Main findings

The current study revealed that the epitope of NIH-CoVnb-112 highly overlaps with the receptor-binding motif of angiotensin-converting enzyme 2 (ACE2) of the host cell – the primary binding site of the spike protein. This result demonstrates the RBD-specificity of CoVnb-112. Interestingly, structural analyses suggested that the recurrent RBD escape mutations are well housed within the nanobody-RBD interface with minor interference of nanobody-RBD contact residues.

Scientists used pseudovirus neutralization assays with lentivirus expressing spike proteins to study the efficacy of the nanobody against SARS-CoV-2 variants. The hamster model validated the fact that NIH-CoVnb-112 is effective against a wide range of SARS-CoV-2 variants. Additionally, an in vitro study using cell culture transduction assay revealed that the nanobody has neutralizing ability against four variants of concern, including the currently circulating Delta variant. The hamster model of SARS-CoV-2 infection treated with nebulized delivery of NIH-CoVnb-112 revealed six orders of magnitude reduction in the viral load, absence of gross weight loss, and prevention of lung pathology. This finding also substantiated the effectiveness of nanobody-based COVID-19 therapeutics.

Previous studies have shown that the hamster model is extremely useful for studying COVID-19 infection. This is because strong viral replication in the respiratory tract and infection causes weight loss and significant lung pathology reliably and consistently. Further, these studies have also demonstrated the ability of nanobodies to prevent SARS-CoV-2 infection in both prophylactic and therapeutic settings in rodent models of COVID-19. However, these studies have used nanobody multimers or nanobody Fc-fusions for intraperitoneal or intranasal instillation delivery and reported a successful decrease in the SARS-CoV-2 viral load in the respiratory tract.

Conclusion

One of the limitations of this study is the use of bio-layer interferometry and pseudovirus assays to measure in vitro binding and neutralization offered by NIH-CoVnb-112. These assays must be interpreted cautiously. Another shortcoming of this study is associated with limitations on sample size, and the results have been represented without statistical analysis.

The authors envisioned the use of nebulized nanobody-based treatments to offer prophylactic protection in healthcare settings. Since this treatment could offer early phase treatment of SARS-CoV-2 infections as well as be administered in home settings, it is likely that it could effectively decrease the severity of the disease. In the future, a purely therapeutic, multidose, or dose-dependent nebulization from the onset of symptomatic infection needs to be performed.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Source

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